1,2,5,6-tetrahydropyridines

ABSTRACT

Disubstituted 1,2,5,6-tetrahydropyridines, e.g., 1,2,5,6tetrahydro-1-methyl-4-(2-morpholino-1-phenylsulfonylethyl)pyridine, are prepared by reducing disubstituted 1,4dihydropyridine with alkali metal hydrides and are useful as antihypertensives.

United States Patent 1191 1111 3,888,853 Manning June 10, 1975 [54] 112ISG'TETRAHYDROPYRIDINES FOREIGN PATENTS OR APPLICATIONS lnvemorl Robe" Manning, Mountain 1,211,691 3/1960 France 260/247.l M

Lakes, NJ.

[73] Assignee: Sandoz, Inc., E. Hanover, NJ. primary Examiner Lorraine Weinberger [22] Filed; Sept 19, 1973 Assistant ExaminerMichael Shippen Attorney, Agent, or FirmGerald D. Sharkm; Robert [21] PP N05 3981582 S. Honor; Thomas O. McGovern Related US. Application Data [63] Continuation of Ser. No. 194,687, Nov. 1, 1971,

abandoned. 57] ABSTRACT Disubstituted 1,2,5,6-tetrahydropyridines, e.g., 1,2,5,- [5%] $5.81. 260/247.l 6 tetrahydro 1 methyl 4 (z morpholino l phenylsul [5 1 [3t- 2 4 l M fonylethyl) pyridine are prepared reducing disub- Fleld of Search u 7. Stituted l4 dihydropyridine metal hydrides References Cited and are useful as antihypertensives.

UNITED STATES PATENTS 2 Claims, No Drawings 3,726,868 4/1973 Manning et a]. 260/247.l R

1,2,5,6-TETRAHYDROPYRIDINES This is a continuation of application Ser. No. 194,687, filed Nov. 1, 1971 now abandoned.

This invention relates to 1,4-disubstituted derivatives of l,2,5,6-tetrahydropyridine. In particular, this invention relates to 1,2,5,6-tetrahydro-l-lower alkyl -4-(2- morpholino-l-ary1sulfonylethyl)-pyridines, intermediates used in their preparation and their use in pharmaceutical compositions.

The compounds of this invention may be represented by the following structural formula:

where n is 0, 1 or 2; R is lower alkyl, i.e., alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, isopropyl and the like and R is halo having an atomic weight of about 19 to 36,

lower alkyl as defined above or lower alkoxy, i.e., alkoxy having 1 to 4 carbon atoms, e.g., methoxy, ethoxy, isopropoxy, etc, and pharmaceutically acceptable thereof.

The compounds of formula (I) are prepared according to the following reaction scheme:

reduction FQ acid addition in) (Pl i where n, R and R are as defined above.

The compounds of formula (ll) are reduced to the corresponding compounds of formula (I) with an alkali metal borohydride reducing agent in a suitable inert solvent. The alkali metal borohydride reducing agents which can be used include sodium, lithium or potassium borohydride, preferably sodium borohydride. Although the reaction temperature is not critical, the reduction is conveniently carried out at temperatures between about 0 to 80C., preferably between 20-40C.

salts G-m 05 0 0 r: -11 (R2 (III) (IV) (v) F O .--'c.i,3

r so (R2)n (II) where The compounds of formula (ll) are prepared bytreating a compound of formula (III) with morpholine (V) in the presence of paraformaldehyde (lV). Although a solvent is not necessary, the reaction is preferably carried out using a lower alkanol such as methanol, ethanol and the like, or ethers, such as tetrahydrofuran, diethyl ether and the like, as solvents or if desired an excess of the compound of formula (V). The temperature at which the reaction is run is not critical, but it is preferred that the process be carried out at temperatures between about l0to C., especially between 20 to 40C. The time of the reaction is not critical, although for optimum results, it should be run for 2 to 20 hours preferably 5 to 15 hours. The final product (II) is recovered by conventional techniques, e.g. filtration and recyrstallization.

The compounds of formula (IV) and (V) and many of the compounds of formula (III) are known and can be prepared by methods disclosed in the literature. The compounds of formula (III) not specifically disclosed in the literature can be prepared by analogous methods from known starting materials.

The compounds of formula (I) are useful because they possess pharmacological activity in animals. In particular, the compounds are useful as hypotensive/anti-hypertensive agents, as indicated by their activity in renal hypertensive rats given mg/kg of active compound using the techniques of A. Grollman (Proc. Soc. Exptl. Biol. and Med. 572102, 1944) and indirectly measuring the blood pressure from the caudal artery in the tail using a pneumatic pulse transducer.

When so utilized, the compounds may be combined with one or more pharmaceutically acceptable carrier or adjuvants. They may be administered orally or parenterally; and depending upon the compound employed and the mode of administration the exact dosage utilized may vary.

Furthermore, the compounds of formula (I) may be similarly administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base,

are readily prepared by reacting the base with an ap propriate acid and, accordingly, are included within the scope of the invention. Representative of the acid addition salts are the mineral acid salts, such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts, such as the succinate, benzoate, acetate, p-toluenesulfonate, benzenesulfonate, and the like.

In general, satisfactory results are obtained when these compounds are administered as a hypotensive/antihypertensive agent at a daily dosage of about 0.5 milligrams to about 100 milligrams per kilogram of animal body weight p.o. This daily dosage is preferably administered 2 to 4 times a day, or in sustained release form. For most large mammals, such as primates, the total daily dosage is from about 35 milligrams to about 750 milligrams. Dosage forms suitable for internal use comprise from about 8.75 milligrams to about 375 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

A representative formulation suitable for oral administration is a tablet or capsule prepared by standard encapsulating techniques which contain the ingredients indicated below and are useful in treating hypertension at a dose of one tablet or capsule 2 to 4 times a day.

Ingredient Weight (mg) tablet capsule l ,2,5,6,-tetrahydro-1methyl-4- (2-mor holino-l-phenylsulfonyl ethyl J-pyridine 25 25 tragacanth l lactose 222.5 275 corn starch 25 talcum 15 magnesium stearate 2.5

Total 300 mg 300 mg.

EXAMPLE 1 l,2,5,6-Tetrahydrol-methyl-4-( 2morpholinol phenylsulfonylethyl)-pyridine Step A: 1,4-dihydrol -methyl-4-( 2-morpholinol phenylsulfonylethyl)-pyridine.

A mixture of 18 grams of l,4-dihydro-l-methyl-4- phenylsulfonylmethylenepyridine, 13.3 grams of paraformaldehyde and 18.4 grams of morpholine in 107 milliliters of ethanol is stirred at room temperature for 17 hours. The resultant solid is collected by filtration and washed with ethanol. Recrystallization from methanol yields 1,4-dihydro-lmethyl-4-(2-morpholino-1- phenylsulfonylethyl)-pyridine (mp. 195C, decomposition).

When the above procedure is carried out using an equivalent amount of l,4-dihydro-1-methyl-4-(pchlorophenylsulfonylmethylene)pyridine; 1,4-dihydrol-methyl-4-(p-tolylsulfonylmethylene)-pyridine or 1,4- dihydrol -methyl-4-( pmethoxyphenylsulfonylmethylene)-pyridine in place of the 1,4-dihydro-1-methyl- 4phenylsulfonylmethylenepyridine used therein there is obtained 1,4-dihydro-1methyl-4-(2-morpholino-l- [p-chlorophenylsulfonyl]-ethyl)-pyridine; 1,4-dihydrol-methyl-4-( 2-morpholinol [p-tolylsulfonyl]-ethyl)- pyridine or 1,4-dihydro-lmethyl-4-(2-morpholino-1- [p-methoxyphenylsulfonyl]-ethyl)-pyridine respectively.

Step B: l,2,5,6-tetrahydro-1methyl-4-(2-morpholinol-phenylsulfonylethyl )-pyridine To a stirred mixture of 14.8 grams of 1,4-dihydro-1- methyl-4-(2-morpholinol phenylsulfonylethyl pyridine in 300 milliliters of methanol at room temper ature is added 7 grams of sodium borohydride in small portions. After addition is completed, stirring is continued for an additional 4 hours. The reaction mixture is evaporated in vacuo and the residue is taken up in ether and water. The ether layer is separated and dried with sodium sulfate. The solvent is then evaporated to crystallize out the product, l,2,5,6-tetahydrol-methyl- 4-( 2-morpholino-1phenylsulfonylethyl)-pyridine(m.p. 110112C).

Ingredients Weight (mg) sterile injectable suspension oral liquid suspension Lil q.s. for injection q.s. to 1 ml.

Io v

ZJI

but

q.s. q.s. to 5 mlv Following the above procedure, but using an equivalent amount of 1 ,4,-dihydro- 1 -methyl-4-( 2- morpholinol -[p-chlorophenylsulfonyl -ethyl pyridine; 1,4-dihydrol -methyl-4-( 2-morpholinol -[ptolysulfonyll -ethyl )-pyridine, or 1,4-dihydro- 1 -methyl- 4-( 2-morpholinol -[p-methoxyphenylsufonyl ]-ethyl pyridine in place of the 1,4-dihydro-l-methyl-4-(2- morpholino-l-phenylsulfonylethyl)-pyridine used therein, there is obtained 1,2,5,6-tetrahydro-l-methyl- 4-(2-morpholino-1-[p-chlorophenylsulfonyl]-ethyl)- pyridine; l,2,5,6-tetrahydrol -methyl-4-( 2- morpholino-l [p-tolylsulfonyl]-ethyl)-pyridine or 1,2,5- ,6-tetrahydrol -methyl-4-(2-morpholinol -[pmethoxyphenylsulfonyl]-ethyl)-pyridine respectively.

The above 1,2,5,6-tetrahydro-1-methyl-4-(2- morpholino-l-phenylsulfonylethyl)-pyridine is dissolved in anhydrous methanol at room temperature. Hydrogen chloride gas is bubbled through the solution for about one-half hour. The hydroscopic dihydrochloride salt obtained is separated by filtration and is dried and stored under anhydrous conditions.

What is claimed is:

l. A compound of the formula I r S0 (1) 2:: 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 which is 1,2,5,6-tetrahydro-1-methyl-4-(2-morpholino-1-phenylsulfonylethyl)-pyridine. 